Researchers conducted a double-blind, placebo-controlled, randomized clinical trial that included 397 adult patients with out-of-hospital cardiac arrest in the Central Denmark Region between January 20, 2020, and April 15, 2021. The last 90-day follow-up was on July 15, 2021. In the study, the intervention consisted of up to two IV or intraosseous doses with 5 mmol of calcium chloride (n = 197) or saline (n = 200), and the first dose was administered immediately after the first dose of epinephrine. The primary outcome was sustained return of spontaneous circulation. The secondary outcomes included survival and a favorable neurological outcome (modified Rankin Scale score of 0-3) at 30 days and 90 days.
The researchers revealed that based on a planned interim analysis of 383 patients, the steering committee halted the trial early due to concerns about harm in the calcium group. Of 397 adult patients randomized, 391 were included in the analyses (193 in the calcium group and 198 in the saline group; average age, 68 [SD, 14] years; 114 [29%] were female). Results revealed that in this randomized clinical trial that included 391 adults with out-of-hospital cardiac arrest, 19% had sustained return of spontaneous circulation after receiving treatment with IV or intraosseous calcium compared with 27% after receiving saline. Moreover, this difference was not statistically significant.
The authors indicated that the trial had numerous strengths, including that administration of the trial drug was blinded and was delivered quickly after the administration of epinephrine, and there were few protocol deviations or use of calcium outside the protocol. The administration of calcium resulted in a clinically significant increase in ionized calcium values upon hospital arrival. The trial included patient-relevant outcomes, including quality of life, and there was no loss to follow-up.
The authors also noted several limitations. First, the trial was halted early and did not reach its preplanned sample size. Even though continuing the trial would have resulted in more precise estimates of the treatment effect, it was not considered ethically justified to continue after the results of the interim analysis were evident. This decision was consistent with the recommendations from the independent data and safety monitoring committee. Second, the trial only tested one dosing regime and timing, and the trial results cannot necessarily be extrapolated to other doses or a different timing interval. Third, the current trial was conducted in the out-of-hospital setting with a relatively long time to drug delivery. The generalizability to the in-hospital setting is therefore uncertain.
The authors concluded that among adults with out-of-hospital cardiac arrest, treatment with IV or intraosseous calcium compared with saline did not significantly improve sustained return of spontaneous circulation. The authors also noted that these results do not support the administration of calcium during out-of-hospital cardiac arrest in adults.
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